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Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD

治疗性抑制干性 AMD 中 Fas 介导的视网膜细胞死亡和炎症

基本信息

批准号：
10093659
负责人：
James T Handa
金额：
$ 61.82万
依托单位：
ONL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093659
关键词：
Acute Address Age related macular degeneration Aging Anatomy Antioxidants Atrophic Autophagocytosis Biotechnology Blindness CD95 Antigens Cause of Death Cell Death Cell Survival Cells Cessation of life Chronic Clinical Clinical Research Clinical Trials Data Decision Making Development Disease Disease Progression Dose Effectiveness Exhibits Exposure to Exudative age-related macular degeneration Eye Foundations Fundus Glaucoma Healthcare High Fat Diet Histologic Impairment Individual Inflammation Inflammatory Injections Innovative Therapy Institutes Investments Literature Measures Mediating Microglia Mitochondria Modeling Mus Natural Immunity Nonexudative age-related macular degeneration Oryctolagus cuniculus Outcome Oxidative Stress Pathway interactions Patient-Focused Outcomes Patients Peer Review Peptides Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Photoreceptors Proteins Quality of life Reproducibility Retina Retinal Detachment Retinal Diseases Role Safety Schedule Signal Transduction Small Business Technology Transfer Research Social Impacts Societies Solid Stress Structure of retinal pigment epithelium Testing Therapeutic Time Toxicology United States Visual Vitamins Work advanced disease baby boomer biological adaptation to stress cigarette smoke cigarette smoke-induced commercial application commercialization economic impact effective therapy effectiveness testing exposure to cigarette smoke gene therapy geographic atrophy human disease improved inhibitor/antagonist interest intravitreal injection macrophage macula neuroprotection novel phase 2 study preclinical development prevent recruit response retinal damage safety study treatment strategy vector

项目摘要

PROJECT SUMMARY / ABSTRACT Age-related macular degeneration (AMD) is the leading, and due to the aging baby boomers, a growing cause of irreversible vision loss in the United States, and is strongly associated with exposure to cigarette smoke (CS) and high fat diets (HFD). While effective treatment is available for neovascular AMD, the AREDS II antioxidant vitamins are the only proven treatment for intermediate dry AMD. Unfortunately, AREDSII is not effective for early or late dry disease, and in intermediate AMD, it merely slows the progression to advanced disease. Treatments that target dry AMD will have a huge impact on the afflicted individual and save billions of health care dollars per year. Impairment of the oxidative stress response, autophagy, mitochondrial function, and the unfolded protein response, as well as dysregulated innate immunity have been implicated in AMD, and thus, have been investigated as treatment targets. Ultimately, these abnormalities cause death of retinal pigment epithelial (RPE) cells and photoreceptors (PR), leading to permanent vision loss. Fas-mediated cell death is the major mechanism of outer retinal cell loss in many retinal diseases including AMD. With no therapy to prevent Fas-mediated outer retinal cell death in AMD, a logical treatment strategy is to prevent Fas- mediated signaling, irrespective of the upstream impairment. ONL Therapeutics, an ophthalmic biotechnology company developing innovative therapies that prevent retinal cell death to improve visual outcomes for patients, has demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model of AMD. Additionally, a gene therapy that inhibits Fas signaling has been developed and tested in acute and chronic models of glaucoma, wherein the vector provided significant inner retinal neuroprotection. Due to the role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stress, this proposal will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMD. Phase I of this Fast- track STTR proposal will i) determine the feasibility of using Fas inhibition to protect against acute CS-induced retinal damage, and ii) demonstrate that the duration of inhibition is clinically meaningful. Phase II will test the ocular safety and effectiveness of repeated intravitreal injections of our peptide Fas inhibitor. In addition, we will test the effectiveness of repeated intravitreal injections of the peptide Fas inhibitor as well as a single intravitreal injection of a Fas inhibitor vector in a novel, peer-reviewed chronic model of atrophic AMD in which apoB100 mice exposed to CS and HFD develop a geographic atrophy phenotype that closely resembles human disease. This proposal combines the expertise of ONL and the Wilmer Eye Institute to test these Fas inhibitors in models of atrophic AMD. Successful execution of the project will support the continued pre-clinical development of the Fas inhibitors for dry AMD and help attract additional investor interest in the company.

项目摘要/摘要